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Abstract

The involvement of oestrogens and related factors in the development
and behaviour of mammary cancer is reviewed. The currently accepted view
is that the selective retention of administered tritium labelled oestradiol
170 by certain mammary tumours is due to the possession of specific
oestradiol binding components similar to those occurring in normal
oestrogen target tissues such as uterus. The possession of such components may be related to the hormone responsiveness of the tumour.
An established method for measuring binding of tritium labelled
oestradiol to human mammary tumours by in vivo infusion (Braunsberg et al..
1967) was set up with the aim of relating this property to the subsequent
progress of the disease in infused patients after surgery, and their
response to endocrine therapy. A method was sought which would reliably
measure specific oestradiol binding in vitro. The first method used
was a steady-state gel filtration method. The use of this method, and its
relative merits, are discussed. Comparative results are presented on
malignant mammary tumours whose binding ability had also been measured in
vivo infusion.
A more rapid and simple procedure became available with the publication of the method of Feherty et al. (1971). This was adopted in favour
of the gel filtration method and the in vivo infusion method was also
stopped. This assay was found to be suitable for measuring oestradiol
binding by DMBA induced rat mammary tumours. The overall results in
human and DMBA tumours and the relevance of these measurements to hormone
responsiveness of tumours are discussed.
Biochemical properties of the binding phenomenon in tumours were
investigated. This was confirmed to be inhibitable by anti-oestrogens,
apparently competitively, and by thiol blocking agents. Thiol containing
compounds affected binding in varying ways:mercaptoethanol and dithiothreitoL
were stimulatory, L-cysteine was inhibitory. The dithiothreitol effect
was further investigated with respect to anti-oestrogen inhibition and the
effect of increased oxygen tension on binding was also studied, these
results being discussed in terras of their relationship to oestradiol
binding, cell division and possible implications in vivo. Attempts to
characterise the tumour binding components by polyacrylamide gel electrophoresis were generally unsuccessful.
The thiol, dihydrolipoic acid, produced transformation of
oestradiol to an as yet unidentified product, occurring as the free
compound and in a water soluble form, apparently sulphate. The properties
of this effect are discussed.
The thesis concludes with a discussion of various proteinsteroid
interactions that occur in the body tissues and fluids
in general, and of specific steroid binding to target tissues
in particular, in terms of molecular models for the mode of
action of steroid hormones based on steroid-"receptor"
interaction.